Genetic and Clinical Characterization of Patients with ADPKD and Intracranial Aneurysms: The PKD-VASC Cohort
Bibliographic record
Abstract
Background: ADPKD is associated with a ~4-5-fold increase in the prevalence of intracranial aneurysm (ICA) compared with the general population. This risk is intensified ~4-fold in ADPKD families with a history of ICA suggesting an inherited predisposition. Methods: To investigate the genetic underpinnings of ICA in ADPKD, we assembled an international cohort of individuals with ADPKD and ICA: the PKD-Vasc cohort. We collected clinical data and DNA for whole exome sequencing (WES) from 289 self-referred participants or colleague-referred de-identified cases with both ADPKD and ICA. Results: The PKD-Vasc cohort is ~70% female and 46% had either a ruptured ICA or required neurosurgical intervention. The remaining 54% had an unruptured ICA of at least 2mm and 22.5% had more than one ICA. Most participants (85%) had a family history of ADPKD and 38% had a family history of ADPKD with ICA. Of note 19% had a history of ICA in a family member without a diagnosis of ADPKD. Most participants (89%) were hypertensive, most had never smoked cigarettes, and a minority (18%) had ESKD at the time of their ICA diagnosis. As has been reported, most unruptured ICA were small (<5mm) and located in the middle cerebral, internal carotid, and anterior communicating arteries. WES identified a PKD1 mutation in 220/289 (76%), a PKD2 mutation in 38/289 (13%) and there was no causative mutation detected in 11%. A small number of cases had disease caused by minor ADPKD genes. These cases were excluded from primary analysis. Among participants with truncating PKD1 variants, 55% had a ruptured ICA or an ICA requiring intervention. We looked at the distribution of truncating and non-truncating PKD1 mutations and we found that variants were scattered along the gene with no obvious genotype/phenotype correlation. Conclusion: Genetic modifiers in the setting of PKD1/PKD2 may influence the risk of ICA. The PKD-Vasc cohort will be a valuable tool for investigating this question. Funding: Other U.S. Government SupportDistribution of PKD1 mutations plotted against their amino acid location within the PKD1 protein.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".